The skin provides the first line of innate immune protection against pathogens by producing antimicrobial peptides (AMPs). Staphylococcus aureus is an important bacterial pathogen that is resisted by AMPs but remains responsible for the majority of serious skin infections in humans. Unfortunately, the growing obesity epidemic has further increased this risk for skin and soft tissue infections, but the mechanism responsible for the decreased defense against microbes is not well understood. This proposal seeks to better understand both normal skin immune defense and why obesity is associated with skin infections by advancing our recent discovery that dermal white adipose tissue (DWAT) is a major source of AMPs in the skin. This potent immune defense function of DWAT was previously unsuspected, but we have shown it to be a key layer for host defense by the skin against S. aureus. Since dysfunction of adipose tissue is known to occur in obesity, we hypothesize that an abnormality in DWAT innate immune functions are part of the loss of function of the adipose in obesity. Our investigations will advance this hypothesis by defining the molecular mechanisms responsible for AMP production by adipocytes and then investigating these functions in mouse models of obesity. This approach will permit us to test our hypothesis that AMP dysfunction in DWAT contributes to increase in S. aureus susceptibility and advance the understanding of fundamental skin immunity. This work may also open new therapeutic avenues for improving the global burden of S. aureus skin infection as compounded by the obesity epidemic. Three aims will be investigated in this project to advance our overall goals: 1. Define how DWAT is activated during host defense. We will determine whether DWAT are activated by bacterial products produced by S. aureus and/or inflammatory signal from the recruited myeloid cells. 2. Define the mechanisms by which DWAT provides cutaneous immune defense. We hypothesize that DWAT influences defense by both producing antimicrobial molecules and modulating inflammation. To test this, we will determine whether cathelicidin is the major antimicrobial peptide produced by adipocytes, and we will also characterize how skin inflammation is regulated by DWAT using mouse models with impaired adipogenesis. 3. Determine the impact of obesity on the innate immune function of DWAT. We hypothesize that AMP dysfunction in DWAT is the key factor driving S. aureus susceptibility in obesity. We will determine how diet-induced obesity (DIO) impairs dermal adipogenesis and we will determine potential therapeutic approach targeting (pre)adipocytes to restore normal skin defense in obesity.